Background
Cervical carcinoma management
Cabozantinib drug
Purpose
Methods / design
Primary outcome
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Efficacy will be assessed by the proportion of patients with disease control rate 3 months after Cabozantinib treatment initiation.
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Safety will be assessed by the proportion of patients with clinical gastro-intestinal (GI) perforation/fistula, GI-vaginal fistula and genito-urinary (GU) fistula events grade ≥ 2 from National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0 criteria.
Secondary outcomes
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The PFS time, defined as the time between initiation of Cabozantinib treatment and progression (RECIST 1.1 criteria) and death of any cause whichever occurs first.
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The ORR defined as the percentage of patients who have achieved complete response or partial response with RECIST 1.1 criteria.
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The OS time, defined as the time between initiation of Cabozantinib treatment and death of whatever cause.
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Toxicities evaluated according to NCI CTCAE version 5.0 criteria, in terms of kind, grade, time of onset, reversibility
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Significant toxicities responsible for interruption or dose reduction of Cabozantinib treatment
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Proportion of patients requiring Cabozantinib dose reduction or treatment stopping for toxicity
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Scores of Quality-of-life (QoL) according to French versions of the self-administered standardized validated questionnaire: EORTC QLQ-C30 and its additional cervix cancer module (QLQ–CX24)
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To investigate nutritional outcomes, including weight, sarcopenia, biological markers, muscle mass, and muscle strength under Cabozantinib in advanced CC
Explorative outcomes
Study population
Inclusion criteria | - Female 18 years of age or older, with histologically confirmed recurrent unresectable or metastatic cervix carcinoma with squamous cell, adenocarcinoma or adenosquamous histology. |
- Patient may have received at least one prior chemotherapy regimen of platinum-based chemotherapy for recurrence or metastatic disease. Cisplatin given in combination with radiation for a localized disease does not count as a prior chemotherapy. Prior treatment for advanced/metastatic disease with bevacizumab and/or immune checkpoint inhibitors are allowed. - ECOG performance status 0–2 | |
- Measurable disease per RECIST 1.1 | |
- The subject must have recovered to baseline or CTCAE version .5.0 ≤ Grade 1 from clinical toxicities related to any prior treatments, i.e. chemotherapy or pelvis radiation unless AE(s) are clinically non-significant (for example alopecia) | |
- Adequate hematological, renal (Calculated creatinine clearance ≥30 mL/min by the CKD-EPI method) and hepatic function. | |
- Serum albumin ≥3.0 g/dL (≥ 30 g/L) | |
- Left-ventricular ejection fraction ≥50% | |
- Subjects affiliated to the social security system | |
Exclusion criteria | - Clinically significant gastrointestinal abnormalities that may affect absorption of cabozantinib including, but not limited to: malabsorption syndrome, major resection of the stomach or small bowel. |
- Clinically significant gastrointestinal abnormalities that may increase the risk for gastrointestinal bleeding and/or fistula, history of abdominal fistula, perforation or intra-abdominal abscess, gastro-intestinal obstruction | |
- History of any one or more of the following cardiovascular conditions within the past 6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina, coronary artery bypass surgery, symptomatic peripheral vascular disease, class III or IV congestive heart failure, as defined by the New York Heart Association. | |
- History of cerebrovascular accident including transient ischemic attack within the past 6 months. Subjects with recent DVT or asymptomatic pulmonary embolism who have been treated with therapeutic anti-coagulating agents for at least 4 weeks are eligible. | |
- Corrected QT interval (QTc) > 500 msec. | |
- Uncontrolled hypertension defined as systolic blood pressure of > 150 mmHg or diastolic blood pressure of > 100 mmHg despite an optimal treatment. | |
- Major surgery or trauma within 28 days prior to first dose of investigational product and/or presence of any non-healing wound, fracture, or ulcer. | |
- Evidence of active bleeding or pathologic conditions that carry high risk of bleeding such as known bleeding disorders, coagulopathy or tumor involving major vessels. | |
- Presence of brain metastases or epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 3 months before inclusion. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of inclusion. | |
- Concomitant use of known strong cytochrome 3A4 inhibitors or inducers. | |
- Patients with second primary cancer, except adequately treated non-melanoma skin cancer, or other solid tumors curatively treated with no evidence of disease for ≥3 years |
Study sites
INVESTIGATORS | PARTICIPATING FRENCH COMPREHENSIVE CANCER CENTRES |
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Investigateur principal: Dr. Elodie COQUAN Co-investigateurs: Pr Florence JOLY Dr. Emeline MERIAUX Dr. Pierre-Emmanuel BRACHET Dr. Mélanie DOS SANTOS Dr. Georges EMILE Dr. Isabelle BONNET Dr. Alison JOHNSON | Centre François Baclesse, CAEN |
Investigateur principal: Pr Isabelle RAY-COQUARD Co-investigateurs: Dr. Olivier TREDAN Dr. Lauriane EBERST Dr. Philippe TOUSSAINT | Centre Léon Bérard, LYON |
Investigateur principal: Dr. Jean-Sébastien FRENEL Co-investigateurs: Dr. Dominique BERTON Dr. Ludovic DOUCET Dr. Emmanuelle BOURBOULOUX Dr. Carole GOURMELON Dr. Pauline DU RUSQUEC Dr. Audrey ROLLOT Dr. Judith RAIMBOURG Investigateur principal: Dr. Sophie ABASIE LACOURTOISIE Co-investigateurs: Dr. Frédéric BIGOT Dr. Victor SIMMET Dr. Patrick SOULIE Dr. Anne PATSOURIS Dr. Paule AUGEREAU Dr. Elouen BOUGHALEM Dr. Margot NOBLECOURT | Institut de Cancérologie de l’Ouest, site NANTES Institut de Cancérologie de l’Ouest, site ANGERS |
Investigateur principal: Dr. Coraline DUBOT Co-investigateurs Dr. Manuel RODRIGUES Dr. Sophie FRANCK Dr. Anne DONNADIEU Dr. Diana BELLO-ROUFAI Dr. Patricia TRESCA Pr Roman ROUZIER Dr. Eugénie GUILLOT Dr. Delphine HEQUET Dr. Claire BONNEAU | Institut CURIE, PARIS |
Investigateur principal: Dr. Cyril ABDEDDAIM Co-investigateurs: Dr. Annick CHEVALIER-PLACE Dr. Valérie CHEVALIER EVAIN | Centre Oscar LAMBRET, LILLE |
Investigateur principal: Dr. Fanny POMMERET Co-investigateurs: Dr. Patricia PAUTIER Dr. Emeline COLOMBA-BLAMEBLE Dr. Alexandra LEARY | Gustave Roussy, VILLEJUIF |
Investigateur principal: Pr Véronique D’HONDT Co-investigateurs: Dr. Michel FABBRO | Institut régional du Cancer, MONTPELLIER |
Study treatments and procedures
Before inclusion within 28 days before drug initiation | During treatment (1 cycle = 28 days) | End of treatment 30 days after the last dose of study treatment (+/− 7 days) | Follow-up every 3 months up to progression | Overall survival after disease progression | ||||||
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Cycle 1 | Cycle 2 | Other Cycles from cycle 2 | Additional Assessment at D1C4 and every 3 cycles (D1C7, D1C10 …) (within 7 days) | |||||||
D1 | D15 | D1 | D15 | D1 | ||||||
Study drug administration | CABOZANTINIB treatment (in a 28 day-cycle) | |||||||||
Informed Consent should be done before any study procedures | ✓ | No study visit is required. The following treatment is at the discretion of physician | ||||||||
Clinical assessment - Complete physical examination including gynecological examination, weight, height (only at baseline), ECOG, vital signs - Adverse Events collection and concomitant treatments | ✓ | ✓ | ✓ ✓ | ✓ ✓ | ✓ ✓ | ✓ ✓ | ✓ ✓ | ✓ ✓ | ||
Laboratory Assessments1 - Blood assessment - Urinary assessment | ✓ within 14 days before drug initiation | ✓3 | ✓ within 3 days | ✓ within 3 days | ✓ within 3 days | ✓ within 3 days | ✓ within 3 days | ✓ within 3 days | ||
Cardiac assessment - ECG (QT interval) - Cardiac Echography or MUGA | ✓ ✓ | ✓ | ✓ | |||||||
Quality-of-life assessment EORTC QLQ-C30 / CX24 | ✓ | ✓ | ✓ | |||||||
Diary card | ✓4 | ✓ | ✓ | |||||||
Radiological assessment - CT-scan (thorax, abdominal and pelvis) 6 - Pelvic MRI 2 | ✓ ✓ | within 3 days ✓ ✓ | +/− 7 days ✓ ✓ | +/− 14 days ✓ ✓ | ||||||
Biological collections - Tumoral biopsy optional5 - Blood samples | ✓ ✓ | ✓ | ✓ | ✓at progression |
Statistical design overview
Sample size calculation
Statistical analyses
Patient reported outcomes
Data monitoring committee
Data management
Withdrawal from study
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Disease progression
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Need to initiate another anti-tumor treatment (e.g., systemic anticancer treatment palliative radiation and surgery)
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Unacceptable toxicity, not compatible with study treatment
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Necessity for withholding study drug for greater than 4 weeks for study-treatment related AEs.
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Significant noncompliance with the protocol schedule in the opinion of the investigator or the Sponsor.
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Patient’s decision (the data already collected during the search can be kept and exploited unless the patient opposes it)
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Intercurrent illness or other reason that requires stopping treatment of the study
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Patient lost to view
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Investigator’s decision